Title:Hsp90 Inhibitors as Anti-Cancer Agents, from Basic Discoveries to Clinical Development
Volume: 19
Issue: 3
Author(s): Shiro Soga, Shiro Akinaga and Yukimasa Shiotsu
Affiliation:
Keywords:
Hsp90, cancer, molecular target therapeutics, chaperone, oncogenic kinases, tumor growth, monoclonal antibodies, geldanamycin (GA), radicicol (RD), clinical trials.
Abstract: Heat shock protein (Hsp) 90 is an ATP-dependent molecular chaperone which stabilizes various oncogenic kinases, including
HER2, EGFR, BCR-ABL, B-Raf and EML4-ALK, which are essential for tumor growth. Several monoclonal antibodies and small molecule
kinase inhibitors which target these kinases have been identified as potential new molecular target therapeutics. Previous reports
have shown that many oncogenic proteins essential for cancer transformation are chaperoned by the Hsp90 complex, and some of these
client proteins have been discovered by using Hsp90 inhibitors, such as geldanamycin (GA) and radicicol (RD).Thus far more than 200
client proteins have been identified. In past derivatives of these natural products have been evaluated in clinical trials, but none of the 1st
generation of Hsp90 inhibitors has been approved yet because of their limitations in physico-chemical properties and/or safety profiles.
However, recent reports have indicated that more than 10 new agents, 2nd generation of Hsp90 inhibitors with different chemotypes from
GA and RD, have entered clinical trials and some of them showed clinical efficacy.
In this review article, we describe the discoveries of major Hsp90 client proteins in the cancer field by RD derivatives, the history of
KW-2478 discovery and development by Kyowa Hakko Kirin, and gave an update on the current status of new Hsp90 inhibitors in clinical
trials.
